Preparation of Building Blocks for Iterative Suzuki-Miyaura Reactions via Direct Bromination of Aryl Boronic Acids: One-Pot Total Syntheses of Dictyoterphenyls A and B

Article abstract of DOI:10.1002/adsc.201700733

A highly efficient method for the preparation of 4-alkoxy-3-bromophenyl boronic acid N-methyliminodiacetic acid (MIDA) esters as building blocks in iterative Suzuki-Miyaura reactions from the 4-alkoxyphenylboronic acids is described using a boronic acid m

Full text of DOI:10.1002/adsc.201700733

Title: Preparation of Building Blocks for Iterative Suzuki-Miyaura
Reactions via Direct Bromination of Aryl Boronic Acids: One-Pot
Total Syntheses of Dictyoterphenyls A and B
Authors: Chun-Young Lee and Cheol-Hong Cheon
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700733
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Preparation of Building Blocks for Iterative Suzuki-Miyaura
Reactions via Direct Bromination of Aryl Boronic Acids: One-
Pot Total Syntheses of Dictyoterphenyls A and B
Chun-Young Leea,b and Cheol-Hong Cheona*
a
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
Tel: +82-2-3290-3147; Fax: +82-2-3290-3121; E-mail: cheon@korea.ac.kr.
Research Institute for Natural Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of
b
Korea
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
12 and 11 steps, respectively.[2] However, considering
Abstract. A highly efficient method for the preparation of
4-alkoxy-3-bromophenyl
boronic
acid
N- the size and complexity of these natural products, it
seemed that the previous total synthesis of
dictyoterphenyls A (1) and B (2) might require
relatively lengthy synthetic sequences, presumably
due to the lack of general methods available to access
the meta-terphenyl structure.
methyliminodiacetic acid (MIDA) esters as building blocks
in iterative Suzuki-Miyaura reactions from the 4-
alkoxyphenylboronic acids is described using a boronic
acid moiety as a blocking group in bromination reactions.
With these MIDA boronates, the total syntheses of
dictyoterphenyls A and B were developed in only two
separate one-pot operations. Furthermore, we have
developed a more practical protocol for the preparation of
meta-terphenyl natural products by simply adding the
second aryl halide and water to the reaction mixture via the
controlled release technique.
Keywords: Blocking Group; Dictyoterphenyls A and B;
Iterative Suzuki-Miyaura reaction; MIDA Boronates; Pot-
economy
Figure 1. Structures of Dictyoterphenyls A (1) and B (2).
Herein, we describe the development of a new
approach to access meta-terphenyl natural products
via iterative Suzuki-Miyaura reactions.[3-8] The direct
bromination of 4-alkoxyaryl boronic acid N-
methyliminodiacetic acid (MIDA) esters where a
MIDA boronate moiety served as a blocking group
provided meta-bromoaryl MIDA boronates as
building blocks for iterative Suzuki-Miyaura
reactions.[9] Using these building blocks, the total
syntheses of dityoterphenyls A (1) and B (2),
representatives of meta-terphenyl natural products,
were completed through iterative Suzuki-Miyaura
reactions in only two separate one-pot operations.
Since there have been no general methods to
access the meta-terphenyl scaffold, we planned to
develop a general synthetic route that could be
applicable to the synthesis of various meta-terphenyl
natural products. To showcase our approach,
dictyoterphenyls A (1) and B (2) were chosen as the
Natural terphenyls, aromatic hydrocarbons consisting
of a chain of three benzene rings, have attracted
considerable attention from the synthetic and
pharmaceutical communities, since some of them
display interesting biological activities.[1] Although
most naturally occurring terphenyls are para-
terphenyl derivatives, some meta-terphenyl natural
products have been isolated from plants. Since these
meta-terphenyls also exhibit interesting biological
activities, the total syntheses of these natural products
have been considered an important field of research
to obtain a sufficient amount of materials for further
biological evaluation.
For example, dictyoterphenyls A and B (1 and 2, Fig.
1), recently isolated from the cellular slime mold
Dictyostelium polycephalum by Kikuchi and co-
workers, were found to display interesting biological
activities including
a
cancer-cell selective
representative target molecules for meta-terphenyl
natural products. The retrosynthetic analysis for
dictyoterphenyls A (1) and B (2) is depicted in
Scheme 1. Dictyoterphenyls A (1) and B (2) could be
antiproliferative activity.[2] Soon after their isolation,
the first total syntheses of dictyoterphenyls A (1) and
B (2) were completed by the same research group in
1
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
readily prepared via Suzuki-Miyaura coupling
reactions between biphenyl boronic acid 4 and an aryl
bromide (3a or 3b). Biphenyl boronic acid 4 could
also be prepared via the Suzuki-Miyaura coupling
reaction between 4-hydroxyphenyl boronic acid 5a
and aryl bromide 6 carrying an additional boronic
acid functionality at the meta-position.
functional groups at the proper positions followed by
the installation of a boronic acid moiety at the more
reactive halogen group.[5],[7] Subsequent protection of
the boronic acid moiety with a proper ligand led to
building blocks suitable for iterative Suzuki-Miyaura
reactions, which generally requires relatively lengthy
syntheses and suffers from moderate yields of the
resulting boronic acids.
Scheme 2. Comparison of Conventional Approaches with
Our Work in Preparation of Building Blocks for Iterative
Suzuki-Miyaura Reactions.
Scheme 1. Retrosynthetic Analysis of Dictyoterphenyls A
(1) and B (2).
The key to the success of this approach would be
the selective formation of biphenyl boronic acid 4
from 4-hydroxyphenyl boronic acid 5a and aryl
bromide 6 via Suzuki-Miyaura coupling reaction
without the formation of the homo-coupled product
of 6.[10] In order to accomplish the desired hetero-
coupled Suzuki-Miyaura reaction between 5a and 6,
the reactivity of the boronic acid present in 6 must be
modulated as an off-state during the Suzuki-Miyaura
reaction between 5a and 6.[3] Furthermore, the
masked reactivity of the boronic acid in the resulting
cross-coupled biphenyl 4 must then be restored as an
on-state to undergo the next Suzuki-Miyaura reaction
with compound 3 to generate the meta-terphenyl
scaffold. Since several known methods have been
developed to control the reactivity of the boronic acid
functional group in iterative Suzuki-Miyaura
coupling reactions by decreasing the Lewis acidity of
the boron atom via complexation with a strong π-
donor ligand[7] or conversion of the sp2 hybridization
of the boron atom to sp3 with a tridentate ligand,[4-6]
there was little concern over the feasibility of
preparing the meta-terphenyl scaffold via iterative
Suzuki-Miyaura reactions.
The more serious challenge in our approach was
the preparation of aryl bromide 6 carrying a boronic
acid moiety at the meta-position to the bromide
substituent. Although meta-halogenated aryl boronic
acids 6’ with a controlled reactivity have been
previously prepared as building blocks for iterative
Suzuki-Miyaura reactions, these building blocks
possess a boronic acid moiety ortho to the other
substituent (R) and the halide functionality is
incorporated at the para-position (Scheme 2a). In
addition, most of the substrates were prepared
through introduction of two different halogen
Recently, we have developed a new method for the
synthesis of ortho-functionalized electron-rich arenes
from the corresponding para-substituted aryl boronic
acids using a boronic acid moiety as a blocking group
in electrophilic aromatic substitution (EAS) reactions
followed by the removal of the boronic acid moiety
through metal-free thermal protodeboronation of the
boronic acid.[9] In these studies, we found that a
decrease in the Lewis acidity of the boron atom in the
boronic acid moiety significantly decreased the
reactivity
towards
ipso-substitution
via
halodeboronation,[11] causing the boronic acid moiety
to behave as a blocking group in EAS reactions.
Since a decrease in the Lewis acidity of the boron
atom in a boronic acid was found to be beneficial
both for a masking strategy in iterative Suzuki-
Miyaura reactions[3] and for a blocking strategy in the
EAS reactions,[9] we envisioned that substrates for
iterative Suzuki-Miyaura reactions could be prepared
from the corresponding boronic acids with a suitable
protecting group using a boronic acid moiety as a
blocking group via EAS reactions. Particularly, since
MIDA boronates of aryl boronic acids have been
utilized as masking groups in iterative Suzuki-
Miyaura coupling reactions,[4-6] we hypothesized that
if a MIDA boronate moiety in MIDA boronates
derived from para-substituted phenyl boronic acid
derivatives acted as a blocking group in bromination
reactions, the bromination reactions would take place
at the ortho-position to the substituent (R) leading to
MIDA boronates of 3-bromo-4-substituted phenyl
boronic acids 6’’ as new building blocks for the
iterative Suzuki-Miyaura coupling reactions (Scheme
2b).
Based on this idea, we began our research with the
preparation of MIDA boronates of meta-bromoaryl
2
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
boronic acids using a boronic acid moiety as a
blocking group in EAS reactions (Scheme 3).
an additional alkoxy group and, in every case,
obtained the desired brominated MIDA boronates 8
in high yields. It should be noted that bromoaryl
MIDA boronates 8, key building blocks for iterative
Suzuki-Miyaura reactions, could be prepared from
commercially available aryl boronic acids in high
yields with very simple operations.
With these compounds 8 in hand, we first
attempted to demonstrate the advantages of our
protocol in the total synthesis of dictyoterphenyl A
(1) (Scheme 4).
Scheme 3. Preparation of Building Blocks in the Iterative
Suzuki-Miyaura Reaction Using a MIDA Boronate Moiety
as a Blocking Group in Bromination Reactions.
Particularly, since most meta-terphenyl natural
products including dictyoterphenyls A and B possess
a hydroxy group in the middle phenyl ring, we first
attempted to prepare substrates from MIDA
boronates of 4-hydroxyphenyl boronic acid
derivatives. MIDA boronate 7a was readily prepared
by the condensation reaction of 4-hydroxyphenyl
boronic acid 5a with MIDA using azeotropic
distillation.[12] Interestingly, the resulting MIDA
boronate 7a could be obtained in a quantitative yield
via recrystallization in common organic solvent.[13]
Next, 7a was subjected to bromination with a
stoichiometric amount of bromine. Although the
MIDA boronate moiety perfectly worked as a
blocking group in an electrophilic bromination
reaction, the desired 2-brominated product 8a was
obtained along with the 2,6-dibrominated product
8a•Br and starting material 7a remained unreacted in
the reaction mixture. This result suggested that the
hydroxy substituent in 7a was too reactive to
selectively control the mono-bromination reaction.
Thus, we decided to protect the phenolic hydroxy
group in boronic acid 5a to decrease the reactivity
toward bromination reaction.[14] Similar to boronic
acid 5a, the corresponding MIDA boronates 7
derived from para-alkoxyphenylboronic acids were
easily prepared in quantitative yields via simple
recrystallization.[13] When these MIDA boronates 7
were subjected to bromination with Br2, the MIDA
boronate moiety perfectly acted as a blocking group
and the bromination successfully took place at the
ortho-position to the protected hydroxy group to
provide the meta-brominated MIDA boronates 8 in
high yields. Under these conditions, we investigated
further the bromination reactions of MIDA boronates
of 4-alkoxyphenyl boronic acid derivatives bearing
Scheme 4. Total Synthesis of Dictyoterphenyl A (1).
Suzuki-Miyaura coupling reaction of meta-
bromoaryl MIDA boronate 8b with boronic acid 5b
in the presence of a palladium catalyst under
anhydrous conditions provided biphenyl MIDA
boronate 9. After concentrating the reaction mixture
of the first reaction, biphenyl product 9 was subjected
to the second Suzuki-Miyaura reaction with aryl
bromide 10 in a mixture of dioxane and H2O via a
controlled release technique[5],[15] to provide terphenyl
compound 11 in 70% yield from 8b after one column
separation operation. Conversion of the ester group
into an amide followed by deprotection of the MOM
groups with HCl provided dictyoterphenyl A (1) in
51% yield over two steps. Overall, we completed the
total synthesis of dictyoterphenyl A (1) in 36 % yield
by only two separate one-pot operations.[16]
With a successful result on the total synthesis of
dictyoterphenyl A (1), the total synthesis of
dictyoterphenyl B (2) was attempted via the same
protocol (Scheme 5). In this case, the same protocol
was followed using of methoxy protected MIDA
boronate 8c in place of MOM protected analogue 8b.
Suzuki-Miyaura coupling reaction of MIDA boronate
8c with boronic acid 5c provided biphenyl MIDA
boronate product 12. Without complete isolation of
12, the crude product of 12 was further subjected to
the second Suzuki-Miyaura reaction with aryl
bromide 10 in a mixture of dioxane and H2O to
provide the desired terphenyl compound 13 in 79%
yield from 8c after one-column separation. Removal
of all the methoxy groups with an excess amount of
3
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
BBr3 provided dictyoterphenyl B (2) in 78% yield.
Overall, the total synthesis of dictyoterphenyl B (2)
was accomplished in 62 % yield.
13.[17] After extracting the reaction mixture, direct
treatment of the resulting crude product of 13 with
BBr3 afforded dictyoterphenyl B (2) in 26% yield
after only one-column separation. In addition, we
further attempted to apply the one-pot protocol to the
synthesis of dictyoterphenyl A (1). Suzuki-Miyaura
reaction of MIDA boronate 8b with boronic acid 5b
under anhydrous conditions provided biphenyl MIDA
boronate 9. Unlike the synthesis of dictyoterphenyl B
(2), the second Suzuki-Miyaura reaction of biphenyl
MIDA boronate 9 with 10 did not occur by simply
adding compound 10 and H2O to the reaction mixture.
However, simply addition of SPhos ligand to the
above reaction mixture afforded meta-terphenyl
compound 11 in 53 % yield after one-column
separation.
In conclusion, we have developed a highly
efficient method for the preparation of building
blocks for iterative Suzuki-Miyaura reactions from
the MIDA boronates of commercially available para-
alkoxy substituted aryl boronic acids through
electrophilic aromatic bromination reactions using a
MIDA boronate moiety as a blocking group in
bromination reactions. Various types of 4-
alkoxyphenyl boronic acids were applicable to this
protocol and the desired 4-alkoxy-3-bromophenyl
MIDA boronates were obtained in excellent yields.
With these building blocks in hand, the total
syntheses of dictyoterphenyls A (1) and B (2) were
completed in 36% and 62% yields, respectively, with
only two separate one-pot operations. Furthermore,
we have developed a more practical protocol for the
preparation of meta-terphenyl natural products by
simply adding the second aryl halide and H2O to the
reaction mixture via the controlled release technique.
Further application of these building blocks to the
synthesis of other natural products via the iterative
Suzuki-Miyaura coupling reaction is currently
underway in our laboratory and will be reported in
due course.
Scheme 5. Total Synthesis of Dictyoterphenyl B (2).
Although we completed the total syntheses of
dictyoterphenyls A (1) and B (2) in only two separate
one-pot operations, there were still some rooms for
improvement of our protocol. Particularly, we had to
change the reaction media from THF into a mixture
of dioxane and H2O for the second Suzuki-Miyaura
reaction, and use a different phosphine ligand for the
second coupling reaction. Thus, we further
investigated the possibility to carry out the second
Suzuki-Miyaura reaction in the same pot by simply
adding the reagents (i.e., aryl bromide 10 and H2O) to
the reaction mixture without any other extra
operations (Scheme 6).
Experimental Section
General procedure for the preparation of building blocks
for the iterative Suzuki-Miyaura reaction (Scheme 3): To a
solution of aryl boronic acid 5 (1.0 mmol) in a mixture of
DMSO and toluene (1:10, 30 mL) were added MIDA (0.44
g, 3.0 mmol) and molecular sieves (4 ꢀ, 0.50 g). The
reaction mixture was refluxed with azeotropic removal of
water using Dean−Stark condenser under an ambient
atmosphere. After 16 h, the reaction mixture was cooled to
room temperature and filtered to remove molecular sieves.
Water was added to the filtrate and the resulting mixture
was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The resulting solid
was dissolved in acetone and reprecipitated in hexanes to
provide the corresponding MIDA boronate 7.
Scheme 6. One-Pot Total Syntheses of Dictyoterphenyls A
(1) and B (2).
Suzuki-Miyaura reaction of MIDA boronate 8c
with boronic acid 5c under anhydrous conditions (in
THF solution) provided biphenyl MIDA boronate 12,
which was subjected to the second Suzuki-Miyaura
reaction by simply adding aryl bromide 10 and H2O
to the reaction mixture via the controlled release
technique to afford the desired terphenyl compound
To a solution of the resulting MIDA boronate 7 (1.0 mmol)
in anhydrous DMF (20 mL) was added Br2 (0.16 g, 1.0
mmol) dropwisely under N2 atmosphere. After complete
consumption of compound 7, the reaction mixture was
quenched with saturated aqueous Na2S2O3 and diluted with
ethyl acetate. The organic layer was separated, and then the
aqueous layer was extracted with ethyl acetate a couple of
4
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
times. The combined organic layers were washed with
brine, dried over MgSO4 and concentrated under reduced
pressure. The residue was dissolved in acetone and
reprecipitated from hexanes to give the brominated MIDA
boronate 8.
[8] There was another excellent approach for tandem
Suzuki-Miyaura coupling reaction based on the
reactivity of a boronic acid functionality. See: C. P.
Seath, J. W. B. Fyfe, J. J. Molloy, A. J. B. Watson,
Angew. Chem. 2015, 127, 10114; Angew. Chem. Int. Ed.
2015, 54, 9976.
Acknowledgements
[9] a) C.-Y. Lee, S.-J. Ahn, C.-H. Cheon, J. Org. Chem.
2013, 78, 12154; b) S.-J. Ahn, C.-Y. Lee, N.-K. Kim,
C.-H. Cheon, J. Org. Chem. 2014, 79, 7285.
This work was supported by the National Research Foundation of
Korea (NRF) grants funded by the Korean Government (NRF-
20100020209 and NRF-2015R1D1A1A01057200). C.-H.C. also
thanks for a financial support from an NRF grant funded by the
Korean Government (NRF-2014-011165, Center for New
Directions in Organic Synthesis).
[10] For an example of homo-coupling reaction of 5-
bromo-2-methoxyphenyl boronic acid, see: S. Punna, D.
D. Díaz, M. G. Finn, Synlett 2004, 2351.
[11] For an example of ipso-substitution of aryl boronic
acids via halodeboronation, see: R. H. Szumigala, Jr., P.
N. Devine, D. R. Gauthier, Jr., R. P. Volante, J. Org.
Chem. 2004, 69, 566.
References
[1] For a review on terphenyl natural products, see: J.-K.
Liu, Chem. Rev. 2006, 106, 2209.
[12] For the preparation of MIDA boronates, see ref 5.
[13] For detailed procedure, see Supporting Information.
[2] H. Kikuchi, Y. Matsuo, Y. Katou, Y. Kubahara, Y.
Oshima, Tetrahedron 2012, 68, 8884.
[14] For the substituent effect on the reactivity in
electrophilic aromatic substitution reaction, see: F. C.
Carey, R. J. Sundberg in Advanced Organic Chemistry,
Part A: Structure and Mechanisms, 5th ed. Kluwer
Academic/Plenum Publishers, New York, 2001,
Chapter 3, pp 335-344.
[3] For highlights and a review on the iterative Suzuki-
Miyaura coupling reaction, see: a) M. Tobisu, N.
Chatani, Angew. Chem. 2009, 121, 3617; Angew. Chem.
Int. Ed. 2009, 48, 3565; b) C. Wang, F. Glorious,
Angew. Chem. 2009, 121, 5342; Angew. Chem. Int. Ed.
2009, 48, 5240; c) for a review: L. Xu, S. Zhang, P. Li,
Chem. Soc. Rev. 2015, 44, 8848.
[15] For a recent study on the hydrolytic stability of
MIDA boronates, see: J. A. Gonzalez, O. Maduka
Ogba, G. F. Morehouse, N. Rosson, K. N. Houk, A. G.
Leach, P. H. Y. Cheong, M. D. Burke, G. C. Lloyd-
Jones, Nature Chem. 2016, 8, 1067.
[4] For the seminal report on MIDA boronates, see: E. P.
Gillis, M. D. Burke, J. Am. Chem. Soc. 2007, 129, 6716.
[5]For reviews on MIDA boronates, see: a) E. P. Gillis, M.
D. Burke, Aldrichimica Acta 2009, 42, 17; b) J. Li, A. S.
Grillo, M. D. Burke, Acc. Chem. Res. 2015, 48, 2297.
[16] For a review on the concept of pot-economy, see: Y.
Hayashi, Chem. Sci. 2016, 7, 866.
[6] For recent representative examples of iterative Suzuki-
Miyaura reactions using MIDA boronates as key
building blocks, see: a) S. Fujii, S. Y. Chang, M. D.
Burke, Angew. Chem. 2011, 123, 8008; Angew. Chem.
Int. Ed. 2011, 50, 7862; b) J. Li, M. D. Burke, J. Am.
Chem. Soc. 2011, 133, 13774; c) G. R. Dick, E. M.
Woerly, M. D. Burke, Angew. Chem. 2012, 124, 2721;
Angew. Chem. Int. Ed. 2012, 51, 2667; d) E. M. Woerly,
J. Roy, M. D. Burke, Nature Chem. 2014, 6, 484; e) J.
Li, S. G. Ballmer, E. P. Gillis, S. Fujii, M. J. Schmidt,
A. M. E. Palazzolo, J. W. Lehmann, G. F. Morehouse,
M. D. Burke, Science 2015, 347, 1221.
[17] Although a good method to modulate reactivity of the
boronic acid as on and off states has been developed in
most of the previous iterative Suzuki-Miyaura coupling
reactions, the cross-coupled products were usually
isolated before their uses for the next Suzuki-Miyaura
reactions. Thus, this was one of the rare examples of
iterative Suzuki-Miyaura reaction where two
consecutive coupling reactions were performed in the
same pot without the isolation of any intermediates.
[7] The Suginome group developed another strategy to
control the reactivity of a boronic acid with 1,8-
diaminonaphthalene (DAN). For examples, see: a) H.
Noguchi, K. Hojo, M. Suginome, J. Am. Chem. Soc.
2007, 129, 758; b) H. Noguchi, T. Shioda, C.-M. Chou,
M. Sugimone, Org. Lett. 2008, 10, 377; c) N. Iwadate,
M. Suginome, J. Organomet. Chem. 2009, 694; d) N.
Iwadate, M. Suignome, Org. Lett. 2009, 11, 1899.
5
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10.1002/adsc.201700733
Advanced Synthesis & Catalysis
UPDATE
Preparation of Building Blocks for Iterative
Suzuki-Miyaura Reactions via Direct Bromination
of Aryl Boronic Acids: One-Pot Total Syntheses of
Dictyoterphenyls A and B
Adv. Synth. Catal. Year, Volume, Page – Page
Chun-Young Lee, Cheol-Hong Cheon*
6
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